DOCSLIB.ORG

2614-2625 Research Article Synthon Disconnection Strategy for Th

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
2614-2625 Research Article Synthon Disconnection Strategy for Th Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2012, 4(5):2614-2625 ISSN : 0975-7384 Research Article CODEN(USA) : JCPRC5 Synthon Disconnection Strategy for the Synthesis Design of “Coelenterazine”- A Bioluminescent Marine Natural Product used in Bioassays Chittaranjan Bhanja 1*, Subhendu Chakroborty 2 1Department of Chemistry, Utkal University, Bhubaneswar-751004, Odisha, India 2Department of Chemistry, Ravenshaw University, Cuttack-753003, Odisha, India _________________________________________________________________________________ ABSTRACT Synthon disconnection strategy is a problem solving technique in the planning of organic syntheses. This strategy, developed by Prof. E.J.Corey of Harvard University, plays vital role in the synthesis design of many bioactive natural products used in analytical biochemistry, molecular biology and drug discovery process. Keeping an overview on the published works in both journals and patent literatures, a good number of synthesis schemes have been proposed based on this strategy for a bioluminescent natural product ‘Coelenterazine’ isolated from marine organism jellyfish Aequorea victoria that finds extensive applications in bioassays. The proposed synthesis planning being a theoretical investigation, the actual laboratory execution requires the cross examination of a considerable number of factors such as reactions, reagents and order of events. In actual practice, generally that route is most feasible which is cost-effective, safe, and easy to carry out and gives maximum yield in a short reaction time. Keywords: Anti-oxidant, Bioassays, Bioluminescence, Coelenterazine, Synthon disconnection strategy, Retrosynthetic analysis. _________________________________________________________________________________ INTRODUCTION Organic synthesis is one of the major activities of organic chemists and the planning of synthesis is an intellectual task where chemist’s imagination, art, creativity and knowledge need to be explored. The simplest synthesis of a molecule is one in which the target molecule can be obtained by submitting a readily available starting material to a single reaction that converts it to the desired target molecule. However, in most cases the synthesis is not straightforward; in order to convert a chosen starting material to the target molecule, numerous steps that add, change, or remove functional groups and steps that build up the carbon atom framework of the target molecule may need to be done. A systematic approach for designing synthetic routes to a molecule is promulgated as a result of Prof. E.J.Corey’s developments of ‘synthon disconnection approach’/‘retrosynthetic analysis’[1-3]. Retrosynthetic analysis is a protocol of stepwise breaking of target molecule to starting materials by disconnection of bonds and functional group interchange to a sequence of progressively simpler structures along a pathway just reverse of actual synthesis. Every disconnected part is an idealized fragment, called ‘synthon’. The synthons when joined by known or conceivable synthetic operations result in the formation of target molecule (TM). Retrosynthetic analysis of a target molecule usually results in more than one possible synthetic route. It is therefore necessary to critically assess each derived route in order to choose the single route that is most feasible. In actual practice, generally that route is selected which is cost-effective, safe (the toxicity and reactivity hazards associated with the reactions involved), and 2614 Chittaranjan Bhanja et al J. Chem. Pharm. Res., 2012, 4(5):2614-2625 ______________________________________________________________________________ easy to carry out and produces maximum yield in a short reaction time, when assessing alternative synthetic routes to a molecule. Organic compounds from marine organisms serve as compounds of interest both in their natural form and as templates for design and discovery of bioactive compounds that play important role in analytical biochemistry, molecular biology and drug discovery process. [4-9]. Bioluminescence is the production and emission of light by a living organism as the result of a chemical reaction during which chemical energy is converted to light energy. This phenomenon is exhibited by many marine organisms such as the sea pansy Renilla reniformis , the deep-sea shrimp Oplophorus gracilirostris , jellyfish Aequorea victoria , the squid Watasenia and hydroid Obelia [10-13]. and has been used extensively in different formats for life science research and drug discovery owing to its extremely high sensitivity and nonhazardous nature. The luminescent system of the jellyfish Aequorea victoria consists of the photoprotein aequorin, which contains the molecule “Coelenterazine” fig.1 as a prosthetic group and shows considerable potential in this area. The bioluminescence reaction of coelenterazine involves an oxidative process with molecular oxygen to produce the emission of light. In bioluminescent applications, coelenterazine has been used with the photoprotein aequorin and its recombinant analogues to monitor Ca 2+ concentrations in mammalian cells[14].Analogues of coelenterazine are also used with aequorin to study ion channels and tyrosine kinase receptors[15] Furthermore, fluorescence resonance energy transfer (FRET) assays that use coelenterazine to detect protein-protein interactions have been developed[16]. Aside from being a luminescent compound, Coelenterazine has also been studied for its anti-oxidant properties for protection against the oxygen toxicity in the environment [17]. Coelenterazine is distributed in a very small amount in its natural sources due to which the quantitative extraction and purification is a very difficult task. Therefore, synthetic methodologies for rapid access of this molecule and its templates are highly essential in synthetic organic chemistry/medicinal chemistry, for a better understanding of its chemiluminescent properties and applications in analytical biochemistry. O OH N N N H HO Figure I: Coelenterazine Although a few methods of synthesis of Coelenterazine are well documented in literature [18], some alternative synthetic routs are still required for its commercial success. Keeping an overview on the published works both in journals and patent literatures, an effort has been made to propose a good number of synthesis schemes for Coelenterazine based on synthon disconnection approach /retrosynthetic analysis. To the best of our knowledge, this type of work has not been reported earlier. The choice of this molecule for synthesis planning is obvious as bioassays are routinely works in life science research related to drug discovery. In this profit oriented world, the chemical/ pharmaceutical industries are also vibrant today in search of cost effective scalable synthesis. Moreover with the availability new reagents, chemical reactions, sophisticated new methods of laboratory execution and the application of synthon approach to analyse the target molecules leading to several routes have made it possible to rethink their synthesis for the improvement in existing processes to satisfy the commercial need. EXPERIMENTAL SECTION The structure and information about Coelenterazine as bioluminescent candid has been collected from different books [1, 2]. The proposed synthesis plannings are then exploited in a novel way from the result of its retrosynthetic analysis using the basic principle outlined in the pioneering works of Prof. E.J. Corey. The symbols and abbreviations are synonymous to that represented in book [3].The analysis–synthesis schemes being theoretical propositions; obviously the syntheses have not been executed in the laboratory. The actual laboratory execution requires the cross examination of a considerable number of factors such as reagents, reactions, order of events, economical viability, environmental benign, saftyness, short time and scalable synthesis. 2615 Chittaranjan Bhanja et al J. Chem. Pharm. Res., 2012, 4(5):2614-2625 ______________________________________________________________________________ RESULTS AND DISCUSSION Retrosynthetic Analysis: 1 O O OMe N OH N N N N NH C-N 2 FGI amide H OMe N N N H Protection H C=N + HO MeO imine O O TM 1 MeO 2 3 N NH2 N NH2 N NH2 Me N NH2 C-C BuSn3 FGI C-C N + Br N N + N MeO MeO 2 4 5 6 7 8 OEt S S H OMe FGI S OMe C-C O + Li OMe O O S O S S 3 9 10 11 12 Synthesis: 1 CH N NH N NH N NH2 3 2 2 MeO BuSn N NH2 3 n-BuLi Bu4NBr3,Py 4 + N N CHCl ,r.t. Br N N THF 3 Pd(PPh3)4 5 MeO 2 8 7 6 DMF OEt O S n-BuLi S OMe HgCl ,CH CN Li 10 S OMe 2 3 H OMe S Ca(CO ) H O S 3 2, 2 O O S O 9 3 12 11 O O N NH 2 OMe OH H OMe Con.HCl N N aq.HCl N N + N (TM) O O EtOH,reflux 1,4-dioxane 2 3 N N MeO 1 H H MeO HO Scheme: 1 Regioselective alkylation of 2-amino pyrazin 8 with benzyllithium prepared from toluene 6 & n-butyl lithium in THF, forms 2-amino-3-benzylpyrazine 6. Selective bromination of 6 using tetra-n-butylammonium tribromide(Sato’s method)[19] produces 3-benzyl-5-bromo-2 aminopyrazine 5. Treatment of 5 with organostannane reagent 4 in presence of Pd(PPh 3)4 in DMF undergoes Stille coupling to form 2. p-methoxyphenylglyoxal 3 is prepared from ethyl p-methoxyphenyl acetate 10 by exploring dithiane based-route. Coupling of 2 with glyoxal 3 under acidic condition forms 1.Deprotection of methyl ether group of 1 under mild acidic condition forms the target molecule (TM ). 2616 Chittaranjan Bhanja et al J. Chem. Pharm. Res., 2012, 4(5):2614-2625 ______________________________________________________________________________
Load more

Recommended publications
  • Modern Organic Synthesis an Introduction
    Modern Organic Synthesis an Introduction G. S. Zweifel M. H. Nantz W.H. Freeman and Company Chapter 1 Synthetic Design • What is an ideal or viable synthesis, and how does one approach a synthetic project? • The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). • This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis. 1 1.1 Retrosynthetic Analysis Basic Concept The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI) Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI). Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Synthetic design involves two distinct steps (1) Retrosynthetic analysis (2) Subsequent translation of the analysis into a “forward direction” synthesis. Chemical bonds can be cleaved heterolytically, homolytically, or through concerted transform. 2 Donor and Acceptor Synthons Acceptor synthon Æ carbocation (electrophilic) Donor synthon Æ carbanion (nucleophilic) Table 1.1 Common Acceptor Synthon Synthetic equivalents Common Acceptor Synthon Synthetic equivalents 3 Table 1.2 Common Donor Synthons Common Donor Synthon Synthetic equivalents Retrosynthetic Analysis A Synthesis A 4 Retrosynthetic Analysis B Synthesis B Alternating Polarity Disconnections The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atom of the molecule. The concept of alternating polarities or latent polarities (imaginary chargies) often enables one to identify the best positions to make a disconnection within a complex molecule.
    [Show full text]
  • Protokoll Handledarmöte 2020-02-14
    http://www.diva-portal.org Postprint This is the accepted version of a paper published in Organic Letters. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Citation for the original published paper (version of record): Colas, K., dos Santos, A C., Mendoza, A. (2019) i-Pr2-NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions Organic Letters, 21(19): 7908-7913 https://doi.org/10.1021/acs.orglett.9b02899 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175818 i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addi- tion of Grignard Reagents to Carboxylate Anions Kilian Colas, A. Catarina V. D. dos Santos and Abraham Mendoza* Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106 91 Stockholm (Sweden) Supporting Information Placeholder direct Grignard - carboxylate coupling 1 R MgX + i-Pr2NMgCl•LiCl 1 MgX ( ) R * CO2 i-Pr i-Pr L L O [Mg] N O ideal ( ) * Mg Li (*) sources 1 1 2 R O Cl R R R2 L O ketone [proposed structure] products base R1 OH [in-situ from commercial] ◾ >30 examples ◾ scalable ◾ facile isotopic-labelling ABSTRACT: The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions.
    [Show full text]
  • Amide Activation: an Emerging Tool for Chemoselective Synthesis
    Featuring work from the research group of Professor As featured in: Nuno Maulide, University of Vienna, Vienna, Austria Amide activation: an emerging tool for chemoselective synthesis Let them stand out of the crowd – Amide activation enables the chemoselective modification of a large variety of molecules while leaving many other functional groups untouched, making it attractive for the synthesis of sophisticated targets. This issue features a review on this emerging field and its application in total synthesis. See Nuno Maulide et al., Chem. Soc. Rev., 2018, 47, 7899. rsc.li/chem-soc-rev Registered charity number: 207890 Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue Amide activation: an emerging tool for chemoselective synthesis Cite this: Chem. Soc. Rev., 2018, 47,7899 Daniel Kaiser, Adriano Bauer, Miran Lemmerer and Nuno Maulide * It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives. This results in a considerably reduced reactivity towards nucleophiles. Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts. Received 27th April 2018 However, a significant body of research on the selective activation of amides to achieve powerful DOI: 10.1039/c8cs00335a transformations under mild conditions has emerged over the past decades. This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product rsc.li/chem-soc-rev synthesis, highlighting the synthetic applications and the potential of this approach. Creative Commons Attribution 3.0 Unported Licence.
    [Show full text]
  • Synthesis Infographic (Revised)
    Organic Synthesis A problem–solving guide for Organic Chemistry I/II ? Goal: propose a synthesis of a target molecule H OH N using given starting materials and any other N reagents you need. starting target materials molecule These key strategies should guide your approach:1 Mapping • Systematically label all the atoms in the ? 1 starting materials, then identify those atoms in H OH N 6 N the target molecule 2 4 5 7 6 1 3 5 7 2 3 4 • Use landmarks (heteroatoms, functional groups) to help you Identifying bonds formed/broken ? and atoms added/removed H OH 1 N 6 N Having labeled atoms, it becomes easier to see: 2 4 5 7 6 1 3 5 7 2 3 4 bonds formed: C7–N2 σ, C6–O σ atoms added • where bonds have been formed/broken bonds broken: C6–C7 π atoms removed • where atoms (including protons) have been added/removed ? Regiochemical and stereochemical analysis H OH 1 N 6 N 2 4 5 7 6 • Look for regiochemical patterns that can 1 3 5 7 2 3 4 provide ideas for synthetic strategies target molecule is 1,2–difunctionalized at C6–C7 • Look for changes in configuration at C7–N2 bond formed at less substituted C of propylene stereocenters (not always applicable) reaction: base–catalyzed epoxide opening 1 OH OH 1 Synthon-based retrosynthetic analysis N + N 6 2 4 6 2 4 Construct hypothetical starting materials for 5 7 3 5 7 3 • synthons forming required bonds 1 This process is called constructing synthons, O δ- • + + HN 6 6 δ 2 4 and it is the basis of retrosynthetic analysis 5 7 5 7 3 possible reagents • Synthons are a tool for choosing reagents 1Based in part on strategies observed in successful students’ responses to synthetic Flynn Research Group 2017 – FlynnResearchGroup.com problems on exams; see: Bodé, N.
    [Show full text]
  • Bsc Chemistry
    __________________________________________________________________________________________________ Subject Chemistry Paper No and Title 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No and 2: Synthons, Synthetic equivalents and Title Retrosynthetic analysis Module Tag CHE_P14_M2 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Synthons and Synthetic equivalents 4. Retrosynthetic analysis 5. Summary CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ 1. Learning Outcomes After studying this module, you shall be able to: Know about synthons Know about synthetic equivalents Know about retrosynthetic analysis. Study the steps involved in retrosynthetic analysis. Know the routine for designing the synthesis. 2. Introduction Organic chemistry is a branch of chemistry which deals with the study of carbon and its compounds. The study includes the understanding of synthesis, structure, properties, and reactions of organic compounds.
    [Show full text]
  • CHEM 4000 Topic 2: Functional Group Oriented Bond-Sets
    CHEMISTRY 4000 Topic #2: Functional Group Oriented Bond-Sets Spring 2019 Dr. Susan Findlay Synthons for Polar Bond Formation Once we identify a bond-set (set of retrosynthetic disconnections), we have to be able to generate a corresponding set of forward reactions. (So much so that knowledge of an available set of forward reactions will have heavily influenced choice of bond-set.) Usually, the forward reaction is a polar bond formation so it involves a nucleophile and an electrophile. First, identify which of the two pieces will serve as nucleophile and which will serve as electrophile. X – X C – + H C or + 2 ? In this example, one option should appear substantially better than the other. In some cases, both options are feasible – but you still have to choose one to try first! 2 Synthons for Polar Bond Formation The functional groups in the target will tend to dictate which piece serves as the nucleophile and which serves as the electrophile (hence the term ‘functional group oriented bond-set’). Each piece is referred to as a synthon. The nucleophilic piece is the donor synthon (or d-synthon). The electrophilic piece is the acceptor synthon (or a-synthon). In the example on the previous page, the aromatic ring dictated the choice of donor and acceptor synthons. What if, instead of disconnecting next to the aromatic ring, we had chosen to disconnect at the next C-C bond in the chain? 3 Synthons for Polar Bond Formation Consider the influence of a carbonyl group on a nearby retrosynthetic disconnection. There are three reasonable choices for disconnections in the vicinity of a carbonyl: O O X – + H C 2 O O – C H 2 + X O O – + H C 2 4 See the end of this set of notes for more on reactions corresponding to the third disconnection.
    [Show full text]
  • Synthi: a New Open-Source Tool for Synthon-Based Library Design
    Preprint___________________________ SynthI: a new open-source tool for synthon-based library design Yuliana Zabolotna1, Dmitriy M.Volochnyuk3,6, Sergey V.Ryabukhin4,6, Kostiantyn Gavrylenko5,6, Dragos Horvath1, Klimchuk Olga1, Olexandre Oksiuta3,7, Gilles Marcou1, Alexandre Varnek1,2 * ____________________________________________________________________________________________ Abstract: Most of the existing computational tools for library design are focused on the generation, rational selection, and combination of promising structural motifs to form members of the new library. However, the absence of a direct link between the chemical space of the retrosynthetically generated fragments and the pool of available reagents makes such approaches appear as rather theoretical and reality-disconnected. In this context, here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those two chemical spaces into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining the position and nature of reactive centers. They can be issued from either the “break-up” of reference compounds according to retrosynthetic rules, or real reagents/BBs, after leaving groups transformation. Such an approach not only enables the design of synthetically accessible libraries and analogs generation but also facilitates BB analysis in the medicinal chemistry context. SynthI code is available in https://github.com/Laboratoire-de-Chemoinformatique/SynthI
    [Show full text]
  • Acetylene in Organic Synthesis: Recent Progress and New Uses
    Review Acetylene in Organic Synthesis: Recent Progress and New Uses Vladimir V. Voronin 1, Maria S. Ledovskaya 1, Alexander S. Bogachenkov 1, Konstantin S. Rodygin 1 and Valentine P. Ananikov 1,2,* 1 Institute of Chemistry, Saint Petersburg State University, Universitetsky prospect 26, Peterhof 198504, Russia; [email protected] (V.V.V.); [email protected] (M.S.L.); [email protected] (A.S.B.); [email protected] (K.S.R.) 2 N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, Leninsky prospect 47, Moscow 119991, Russia * Correspondence: [email protected] Received: 16 August 2018; Accepted: 17 September 2018; Published: 24 September 2018 Abstract: Recent progress in the leading synthetic applications of acetylene is discussed from the prospect of rapid development and novel opportunities. A diversity of reactions involving the acetylene molecule to carry out vinylation processes, cross-coupling reactions, synthesis of substituted alkynes, preparation of heterocycles and the construction of a number of functionalized molecules with different levels of molecular complexity were recently studied. Of particular importance is the utilization of acetylene in the synthesis of pharmaceutical substances and drugs. The increasing interest in acetylene and its involvement in organic transformations highlights a fascinating renaissance of this simplest alkyne molecule. Keywords: acetylene; vinylation; cross-coupling; addition reactions; drugs; pharmaceutical substances; biologically active molecule; monomers; polymers 1. Introduction Since the discovery of acetylene, new areas of acetylene chemistry have been continuously developed. The rich scope of chemical transformations available for a C≡C triple bond can be exemplified by coupling [1–5] and addition reactions [6,7].
    [Show full text]
  • Methods of Reactivity Umpolung
    Volume 18 - Number 4 April 1979 Pages 239 - 336 International Edition in English Methods of Reactivity Umpolung By Dieter SeebachL"] Dedicated to Professor Horst Pommer on the occasion of his 60th birthday The past decade of organic chemistry may be characterized as a period of violent development of new synthetic methods. This was accompanied by a systematization of the analysis of synthetic problems (synthetic strategy). The planning of the synthesis of an organic target molecule is greatly facilitated by distinguishing between reagents X(C),, . with normal reactiv- ity (acceptor properties at C'*3,5-, donor properties at X, C2,4-.)and with reactivity umpolung (acceptor properties at X, C2,"...,donorproperties at C',3,5-.).In this context, reactivity umpolung turned out to be useful as a heuristic principle, as a classification scheme, and as an aid for locating so-called strategic bonds (synthon, transform, and antithesis according to E. J. Corey). There are six principal methods of umpolung: 1,2n-oxidation, heteroatom exchange and modification, homologation and its reversal, the cyclopropane "trick", use of acetylenes, and redox reactions; under certain circumstances none of these techniques is necessary in cases where direct umpolung is possible. Throughout the article, normal reactivity is indicated by green print; reactivity umpolung by red print. 1. Postulates and Nomenclature 3. These heteroatoms impose an alternating acceptor and donor reactivity pattern (I upon the carbon skeleton, i.e. Before describing and systematizing the methods of reactiv- acceptor properties or attack by donors at carbons C'.3.5-, ity umpolung, the scope of the discussion, the nomenclature and donor properties or attack by acceptors at carbons of synthetic methodology and the synthetic problem behind C2.4.6.-;the heteroatom Xo itself is a donor center tl"['al.
    [Show full text]
  • Weinreb Amide Based Building Blocks for Convenient Access to Various Synthetic Targets
    Indian Journal of Chemistry Vol. 48B, December 2009, pp. 1749-1756 Weinreb amide based building blocks for convenient access to various synthetic targets B Sivaraman, B N Manjunath, A Senthilmurugan, K Harikrishna & Aidhen Indrapal Singh* Department of Chemistry, Indian Institute of Technology, Madras, Chennai 600 036, India E-mail: [email protected] Received and accepted 16 August 2009 N-Methoxy-N-methylamide, popularly known as the Weinreb amide (WA), has served as an excellent acylating agent for organolithium and/or organomagnesium reagents and a robust equivalent for an aldehyde group. The stability of the WA functionality, its ease of preparation, the scalability of its reactions and its predictable reactivity are the key features responsible for its prominent use in several synthetic endeavors by the chemists world-wide. The development of WA-based building blocks and synthetic equivalents for interesting synthons has been a long drawn pursuit initiated in nineties and through this mini-review accomplishments in this direction, with particular emphasis on the building blocks, developed recently in the last three years are summarized. Keywords: Weinreb amide, building blocks, synthetic equivalent, FTY 720, olefination, sulfone, α-diketones, 4-aryl- tetrahydroisoquinoline N-Methoxy-N-methylamide 1, popularly addressed as in late nineties has come a long way3a. In this mini- the Weinreb amide, has served as an excellent review, our accomplishments in this direction, with acylating agent for organolithium or organomagnesium particular emphasis on the building blocks, developed reagents and as a robust equivalent for an aldehyde recently in last three years have been summarized3. group1. These two aspects have been exploited Although the initial developments of these synthetic exhaustively in various synthetic endeavors2.
    [Show full text]
  • Enantioselective Synthesis of Oasomycin[Emsp14]A, Part II
    Angewandte Chemie DOI: 10.1002/anie.200603654 Natural Products Synthesis Enantioselective Synthesis of Oasomycin A, Part II: Synthesis of the C29–C46 Subunit** David A. Evans,* Pavel Nagorny, Dominic J. Reynolds, and Kenneth J. McRae Dedicated to Professor Y. Kishi on the occasion of his 70th birthday. Syntheses of the C1–C12 and C13–C28 oasomycin A subunits of the elegant studies of Wasserman et al., the decision was were described in the preceding Communication.[1] Herein we made to mask the C46 carboxy terminus in sulfone II as its describe the synthesis and assemblage of the C29–C46 portion derived 4,5-diphenyloxazole,[3] thus preserving its oxidation of this polyketide natural product. According to the synthesis state. The singlet-oxygen-mediated liberation of this carboxy plan,[2] the C29–C46 fragment targeted as aldehyde I is moiety could, in principle, be executed at numerous stages in considered as one of the complex subgoals. the synthesis because of the compatibility of this transforma- Julia disconnection of the D38 olefin in I affords fragments tion with the multitude of other oxygen-protecting groups in II and III of comparable complexity (Scheme 1). On the basis the assembled or partially assembled subunits. The C29–C38 fragment III (Scheme 1) is composed of both polyacetate and polypropionate subunits. The latter motif could be introduced by a SnII-mediated syn-selective aldol addition of dipropionyl synthon IV to aldehyde V—a reaction which was developed by us some years ago.[4] The synthesis of aldehyde V began with a chiralLewis acid catalyzed aldol addition of the Chan diene[5] 1 to benzyloxy acetaldehyde 2 promoted by the CuII complex 3 (5 mol%) that was previously developed by our research group (Scheme 2).[6] The resultant ketoester 4 (95% ee) was [7] reduced with Me4NBH(OAc)3 to afford a 1,3-anti diol (91:9 d.r.).
    [Show full text]
  • Disconnection Approach Retrosynthetic Analysis
    DISCONNECTION APPROCH: Retrosynthetic Principles and Synthetic Applications XV Summer School in Pharmaceutical and Medicinal Chemistry Rio de Janeiro, Brasil 09-13 February 2009 Pier Giovanni Baraldi Department of Pharmaceutical Siences Ferrara University, Italy Disconnection Approach Retrosynthetic Analysis: the logical process of analysing the structure of a target molecule to discern a possible synthesis step by step Retrosynthetic arrow is: A B (B is a precursor of A) ( Means “can be made from”) Functional group interconversion (FGI) Functional group addiction (FGA) Functional group removal (FGR) Disconnection: the formal reverse of a bond forming reaction (conceptual cleavage of a bond to break the molecule into possible starting materials) dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom Reagent: A chemical compound used in practice for a synthon Disconnection Approach Synthons and Reagents dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom. d1 CN d2 CH2CHO an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom. a1 CH2OH a2 CH2CHO a3 CH2CH2CHO Reagent: A chemical compound used in practice for a synthon. Synthon Reagent CH3 CH3I or CH3oTs CH3 CH3MgBr CH2CH2CHO CHO Retrosyhthesis of Benzocaine
    [Show full text]